Liquid paraffin oil and lactulose-based hypocaloric laxative jelly and method for its preparation

ABSTRACT

Paraffin oil and lactulose-based jellied clear laxative emulsion containing from 75 to 85 parts by weight of liquid paraffin oil and from 25 to 15 parts by weight of an edulcorated lactulose aqueous solution. The invention also concerns a method for the preparation of said emulsion.

This application is a continuation of PCT/FR95/00219 published Feb. 25,1995.

SCOPE OF THE INVENTION

The object of the present invention is a new emulsified compositionbased on liquid paraffin oil and lactulose, produced in the form of asmooth, non-sticky jelly and intended for oral administration for thetreatment of constipation in humans.

TECHNOLOGICAL BACKGROUND OF THE INVENTION

Constipation is a common pathological phenomenon which affects aconsiderable number of individuals with no real distinction as to sex orage. Recent publications indicate that this phenomenon chronicallyaffects at least 10% of the French and British populations (Chaussade,S. and Guerre, J., Traitement de la constipation Treatment ofconstipation!, Encycl. Med. Chir., Paris, France, Estomac-Intestin, 9071A¹⁰, 6-1985, 6 pp.; Taylor, R., Br. Med. J., 1990, 300, 1063-64), andthat his percentage is even higher in the United States, Japan, and thenorthern European countries. It is also known that almost 50% of personsafflicted medicate themselves with laxatives, some of which areconsidered potentially dangerous.

Aside from the simplest cases, in which a dietary correction, inparticular by administration of natural or dietetic fiber, is sufficientto correct the situation, it is frequently necessary to apply treatmentby laxative means, one of the oldest and least harmful of which consistsof ingestion of a mineral oil, more particularly liquid paraffin oil.

It is acknowledged that his oil, which is not absorbed, acts by way ofits lubricating and emollient properties, thus promoting the evacuationof feces. This activity has been and still is widely utilized, since theFrench dictionary of pharmaceutical preparations (Dictionnaire Vidal,1993, Editions du Vidal) lists a dozen preparations containing paraffinoils of various viscosities, alone or in association with othercompounds, and offered in liquid or jellied form or as solid powders.

The liquid products are in fact most often pure or flavored paraffinoil. These are the least complex. However, aside from the practicaldifficulties in handling them, administering them to bedridden personsor to young children is tricky, since if difficulties in swallowingexist, involuntary inhalation of them can cause bronchial and/orpulmonary disorders. It is also known that in large doses, these liquidproducts entail undesirable risks of anal leakage and perianalirritation.

Jellied products are easier to handle. They are generally producedeither by mixing liquid paraffin with semi-solid to solid paraffins, orby emulsifying liquid paraffin with an aqueous phase containing suitableexcipients. Regarding emulsions of this kind, in 1921 Rector, in U.S.Pat. No. 1,389,161, described the means for producing transparentemulsions by adjusting the refractive index of the aqueous phase to thatof the oil phase. W. FF. Whitmore and R. E. Linehan (Ind. and Eng.Chemistry, 21, pp. 878-880, 1929) generalize this teaching by describingmodification of the refractive index of one or the other phase to obtainthis transparent state. This principle has generated formulas for avariety of applications, including recently:

European patent application filed on Sep. 9, 1986 and published underno. 216 557 concerns translucent oil-in-water emulsions of semi-solidparaffin, similar in appearance to jelly and intended for application tothe skin. Their aqueous phase contains a humectant agent, and the oilphase an agent suitable for the preparation of water-in-oil emulsionsand semi-solid paraffin (m.p. >38° C.), to which a mineral oil isoptionally added. In the Examples illustrating the invention, the oilphase does not exceed 70%, and the emulsifying agent specific to thewater-in-oil emulsions is dissolved in the oil phase during preparation.

object of the French patent application filed on Jul. 20, 1987 andpublished under no. 2 618 351 is a jellied, transparent oil-in-wateremulsion consisting of 50 to 80% by weight of a hydrophobic oily liquid,0.5 to 5% of a water-soluble surfactant agent, 2 to 10% of ahydrocolloid, water-soluble agents, and water; it is specified that thedifference between the refractive indices of the aqueous and oil phasesis no greater than 0.005. These jellies are intended for culinary orcosmetic use; it is specified that the hydrocolloid is gelatine and thatthe compositions contain not only citric acid, but also either a sugaror glycerol or sorbitol as water-soluble agent. In the Examplesillustrating the invention, the prepared emulsions contain a maximum ofonly 70% by weight of oil phase, and the aqueous phase never containsless than 16% gelatine, or 4.8% by weight in terms of the finalemulsion. It is moreover specified that it is essential, in order toprepare these emulsions with a high concentration of hydrophobic phase,to add the water-soluble surfactant agent at a concentration of 0.5 to5.0% in terms of the jelly. Example 3 of this invention specificallydescribes a jelly which, for 70 parts Vaseline, contains 30 parts of anaqueous solution containing 29% water, 45% citric acid, 1% lauryl ethersulfate, and 25% gelatine, or for this latter constituent, 7.5% in termsof the weight of the final composition; this represents a significantprotein input with regard to both nutrition and the consistency of thejelly, which probably is almost solid in texture.

With respect to the jellied laxative pharmaceutical preparationspresented and listed in the Vidal dictionary (cited above), andregardless of the method for producing them, these products containsucrose to improve their taste, which is noted as a contraindication tothe treatment of constipation in diabetic patients or those on a stricthypocaloric diet. As regards the solid forms that are proposed, productsin which the liquid oil is adsorbed onto a support, or is presented inmicroencapsulated form, are available commercially; these presentationsrequire economically penalizing technologies.

Recently, in the European patent application published under no. 486353, an anhydrous composition is proposed that is characterized by theincorporation of anhydrous lactulose into a mixture of purifiedparaffinic hydrocarbons whose melting point is between 45° C. and 60°C., the relative proportions of the constituents being such that thelaxative activity of the hydrocarbons is said to be limited as comparedto that of the lactulose, whose usual laxative activity is stated to beintensified in the claimed composition. A result of this kind would beworth confirming, since without further information it appears that inthe proposed invention, the anhydrous lactulose is intimately mixed witha mixture of hydrocarbons whose melting point is much higher than thetemperature of the human body, calling into serious question itsavailability in the gastrointestinal tract, and more generally thegustatory acceptability of the product. Moreover at present it cannot beconsidered that lactulose in its anhydrous form is an economically andpractically satisfactory solution, given the technological outlayrequired to produce this product in its solid form and, in that state,its tendency to rehydrate spontaneously in the ambient environment.

In fact none of the solutions that have been proposed or marketed foradministering paraffin oil for laxative purposes is entirelysatisfactory, for practical, economic, or dietetic reasons.

SUMMARY OF THE INVENTION

The present invention resolves this situation by means of a hypocaloricjellied laxative composition with a high concentration of liquidparaffin oil associated with lactulose, which is a non-assimilablesynthetic disaccharide that is itself acknowledged to havenon-aggressive laxative properties.

Departing from the prior art and in particular with the teaching ofFrench patent 2 618 351, the applicant has, surprisingly, producedemulsions which combine approximately 80% by weight of liquid paraffinoil with a sweetened aqueous phase containing lactulose and jellied bymeans of a hydrocolloid, this with the notable exclusion of anysurfactant agent, in order to produce stable, homogeneous jelliedcompositions with a translucent appearance and a smooth, non-stickytexture.

DETAILED DESCRIPTION OF THE INVENTION

The object of the present invention is a new jellied, emulsified, andtranslucent composition characterized in that it consists essentially of75 to 85 parts by weight of liquid paraffin oil and 25 to 15 parts byweight of a sweetened aqueous solution of lactulose containing a totalof 54 to 66% by weight dry matter.

A preferred composition is one in which the liquid paraffin oil, whoserefractive index is between 1.473 and 1.483, represents 76 to 80 partsby weight, for 20 to 24 parts by weight of an aqueous phase whosedry-matter content is 57.5 to 62.5%.

Aside from lactulose which is its major constituent, the aqueous phasealso contains gelatin, organoleptic adjuvants, and optionally anon-assimilable carbohydrate.

A phase of this kind is produced by mixing 90 to 95 parts by weight of alactulose syrup with 2.5 to 5.5 parts of a 20% aqueous solution ofgelatin, 2 to 2.5 parts of a sweetening and coloring mixture, andoptionally a non-assimilable carbohydrate, the dry-matter contentconforming to the specifications indicated above and the refractiveindex of the mixture, determined at 20° C., matching that of theparaffin oil to within ±0.010 units.

More particularly, the lactulose syrup used corresponds to the gradescurrently available commercially, namely lactulose concentrations of 50to 66%. A syrup titrating at 50% is preferred This is a clear, paleyellow syrup for which, at 20° C., the refractive index is between 1.430and 1.490, rotatory power -36° to -44°, and density approximately 1.310.

The gelatin, meeting the specifications of the European Pharmacopeia(2nd ed.; 330, 1986), is used at a concentration of 0.5 to 1.1 parts byweight of the aqueous phase, and preferably 0.65 to 0.85 parts. Themixture intended to sweeten and color the composition comprisesorganoleptic adjuvants necessary for good presentation and goodacceptability of the product, namely, expressed by weight in terms ofthe mixture, approximately 33% citric acid, approximately 60% of aflavoring composition which consists of a mixture of natural and/orartificial raspberry and plum flavors, approximately 5% of a syntheticsweetener such as saccharin sodium, and approximately 2% of a coloringagent such as cochineal red.

The non-assimilable or poorly assimilable carbohydrate additive that isused optionally to adjust the refractive index of the aqueous phase isselected from the class of mono- or disaccharides acknowledged asacceptable for pharmaceutical use and for administration to diabeticpatients. The preferred compound is sorbitol, commonly used as anexcipient and sweetener.

In particular when the dry-matter concentration or refractive index ofthe aqueous phase prepared in this manner prove to be less or greaterthan the standards defined above, they are adjusted by adding thecarbohydrate to raise them, or conversely they are diluted with water todecrease them.

According to the invention, the particularly preferred compositioncorresponds to the following centesimal formula:

    ______________________________________                                        Liquid paraffin oil      78.230 g                                             50% (by weight) lactulose syrup                                                                        16.210 g                                             Powdered sorbitol        4.200 g                                              Citric acid monohydrate  0.150 g                                              Gelatin                  0.160 g                                              Cochineal red A coloring agent                                                                         0.012 g                                              Composition of artificial and natural                                                                  0.300 g                                              raspberry and plum flavors                                                    Saccharin sodium         0.020 g                                              Potable water to make 100.000 g                                               ______________________________________                                    

The invention also relates to a method for preparing an oil-in-wateremulsion of this kind, which consists in introducing the paraffin oil,heated to a temperature of 50° to 80° C., with appropriate agitation,into the aqueous phase which is also heated to a temperature of 40° to70° C. and which comprises all the compounds of the aqueous phase exceptfor the flavor composition, in order to produce a homogeneous andtranslucent jellied emulsion to which the flavoring composition is thenadded, and which is then transferred into a storage tank connected tothe filling machines for distribution of the jelly into glass jars orsingle doses.

More precisely, the method consists in first dissolving the coloringagent in the freshly prepared gelatin solution, then adding it to thelactulose syrup in which the citric acid, the saccharin sodium, andoptionally the sorbitol have previously been dissolved; then secondlypreparing the actual emulsion, which consists in introducing theparaffin oil, previously brought to 50°-80° C. and preferably to 70°C.±5° C., into the aqueous phase prepared as described above, heated to40°-70° C. and preferably to 55° C.±5° C. The flow rate, andconsequently the time required for introduction, of the paraffin oildepend on the agitation efficacy and on the temperature at which theoperation is performed. With "turbine" agitation, introduction can beperformed in a time period of between 3 and 45 minutes. Under thepreferred temperature conditions indicated above the operation can beperformed, assuming effective agitation, in a period of between 5 and 20minutes, after which the flavoring composition is introduced and theproduct yield is then transferred into a storage annex before dividingit into units intended for sale.

EXAMPLES

The examples and experiments described in the technical section belowillustrate the invention and its implementation, but without therebylimiting it.

Example 1 (preferred)

Preparation of a jellied emulsion of centesimal composition:

    ______________________________________                                        Liquid paraffin oil      78.230 g                                             50% (by weight) lactulose syrup                                                                        16.210 g                                             Powdered sorbitol        4.200 g                                              Citric acid monohydrate  0.150 g                                              Gelatin                  0.160 g                                              Cochineal red A coloring agent                                                                         0.012 g                                              Composition of artificial and natural                                                                  0.300 g                                              raspberry and plum flavors                                                    Saccharin sodium         0.020 g                                              Potable water to make 100.000 g                                               ______________________________________                                    

In a first step, 72.945 kg of 50% lactulose syrup that has previouslybeen heated to 60° C.±5° C. is introduced into the apparatus intendedfor preparation of the emulsion, and 0.675 kg of citric acidmonohydrate, 0.090 kg of saccharin sodium, and 18.900 kg of powderedsorbitol are then dissolved into it under moderate agitation.

Separately, 0.054 kg of cochineal red A is dissolved in 3.2 liters ofpotable water, into which 0.720 kg of gelatin meeting the specificationsof the European Pharmacopeia (2nd ed.; 1986) is dispersed. The solutionis left for 20 minutes to swell, and is then heated over a water bath to55° C.±5° C. before adding it to the sweetened solution, as describedpreviously, in the apparatus. The refractive index of the aqueousmixture, measured at 20° C., is 1.4740±0.010.

352.035 kg of liquid paraffin, previously heated to 70° C.±5° C., isthen introduced continuously at a rate of 50±10 liters per minute withagitation, the agitation speed being gradually increased as introductionproceeds so as to ensure continuous incorporation of the added oil intothe homogeneous jellied emulsion.

1.350 kg of a flavoring composition consisting of alcoholates of naturaland artificial raspberry flavors and natural plum flavor is then added;agitation is continued for two minutes, then the emulsion is transferredinto a storage tank connected to a packaging machine for subsequentdistribution into glass jars or plastic cups for single doses.

The jelly prepared in this manner, after cooling to 20° C., is similarto a natural food jelly in its appearance, consistency, andtransparency. The same is true for its handling during administration:it can be cut easily and cleanly with a spoon, and while beingsufficiently firm not to flow off the implement, has a smooth texturewith a pleasant gustatory feel.

Its stability, studied in glass jars at 20° C., is excellent: after 12months its appearance, behavior, and organoleptic characteristics werecompletely retained.

Example 2

Using the method of Example 1, 86.850 kg of 66% (by weight) lactulosesyrup, previously heated to 60° C.±5° C., is introduced into theapparatus intended for preparation of the emulsion, and 0.675 kg ofcitric acid monohydrate, then 0.090 kg of saccharin sodium, are thendissolved in this with moderate agitation.

Separately, 0.054 kg of cochineal red A is dissolved in 8.2 liters ofpotable water, in which 0.720 kg of gelatin is dispersed. Afterswelling, the solution is heated to 55° C.±5° C. over a water bathbefore adding it to the sweetened solution, thus producing an aqueousphase whose dry-matter content is 61%.

352.035 kg of liquid paraffin is then introduced into the mixture withagitation, as described in the previous Example, then 1.350 kg of aflavoring composition consisting of alcoholates of raspberry and plumflavors is added. After two minutes, the jellied emulsion is transferredinto a storage tank before being distributed into units and packaged.

What is claimed is:
 1. A jellied and translucent emulsion, characterizedin that it consists essentially of about 75 to 85 parts by weight ofliquid paraffin oil and 25 to 15 parts by weight of a sweetened aqueoussolution of lactulose containing a total of 54 to 66% by weight drymatter.
 2. The emulsion as defined in claim 1, consisting of 76 to 80parts by weight of liquid paraffin oil with a refractive index between1.473 and 1.483 and 24 to 20 parts by weight of a sweetened aqueoussolution of lactulose containing a total of 57.5 to 62.5% by weight drymatter.
 3. A jellied and translucent emulsion, characterized in that itconsists essentially of about 75 to 85 parts by weight of liquidparaffin oil and 25 to 15 parts by weight of a sweetened aqueoussolution of lactulose containing a total of 54 to 66% by weight drymatter, wherein the sweetened aqueous solution consists essentially of amixture of 90 to 95 parts by weight of a lactulose syrup with 2.5 to 5.5parts of a 20% aqueous solution of gelatin, 2 to 2.5 parts of asweetening and coloring mixture, and optionally a non-assimilablecarbohydrate, the refractive index of the said mixture, determined at20° C., matching that of the paraffin oil to within ±0.010 units.
 4. Theemulsion as defined in claim 1, characterized in that the lactulosesyrup used for preparation of the aqueous solution titrates at 50 to 66%by weight of product.
 5. A jellied and translucent emulsion,characterized in that it consists essentially of about 75 to 85 parts byweight of liquid paraffin oil and 25 to 15 parts by weight of asweetened aqueous solution of lactulose containing a total of 54 to 66%by weight dry matter and 0.5 to 1.1 parts by weight of gelatin meetingthe specifications of the European Pharmacopeia (2nd ed.; 330, 1986). 6.A jellied and translucent emulsion, characterized in that it consistsessentially of about 75 to 85 parts by weight of liquid paraffin oil and25 to 15 parts by weight of a sweetened aqueous solution of lactulosecontaining a total of 54 to 66% by weight dry matter, and consistingessentially of a mixture of organoleptic adjuvants selected from thegroup consisting of citric acid, a flavoring composition of naturaland/or artificial raspberry and plum flavors, saccharin sodium, and acoloring agent.
 7. A jellied and translucent emulsion, characterized inthat it consists essentially of about 75 to 85 parts by weight of liquidparaffin oil and 25 to 15 parts by weight of a sweetened aqueoussolution of lactulose containing a total of 54 to 66% by weight drymatter, and consisting essentially of sorbitol as a carbohydrateadditive to adjust the refractive index of the said solution.
 8. Theemulsion whose composition by weight is:

    ______________________________________                                        Liquid paraffin oil      78.230 g                                             50% (by weight) lactulose syrup                                                                        16.210 g                                             Powdered sorbitol        4.200 g                                              Citric acid monohydrate  0.150 g                                              Gelatin                  0.160 g                                              Cochineal red A coloring agent                                                                         0.012 g                                              Composition of artificial and natural                                                                  0.300 g                                              raspberry and plum flavors                                                    Saccharin sodium         0.020 g                                              Potable water to make 100.000 g                                               ______________________________________                                    


9. A method for preparing a jellied, homogeneous, and translucentoil-in-water emulsion, which comprises introducing, over a time periodof between 3 and 45 minutes, 75 to 85 parts by weight of paraffin oilwhose temperature is from 50° to 80° C. into 25 to 15 parts of anaqueous phase, heated to a temperature of 40° to 70° C., comprising amixture of 90 to 95 parts by weight of a lactulose syrup with 2.5 to 5.5parts of a 20% aqueous solution of gelatin, 2 to 2.5 parts of asweetening and coloring mixture, and optionally a non-assimilablecarbohydrate, the refractive index of the said mixture, determined at20° C., matching that of the paraffin oil to within ±0.010 units, thenadding a flavoring composition and, after transfer, distributing theresulting jellied and translucent emulsion.